The focus of the proposed study is to determine the role of IRF transcription factors in the innate response to HIV-I infection. Over the past few years we have identified and characterized three novel IRFs: IRF-3, IRF-5 and IRF-7. We have shown that these factors serve as direct transducers of virus mediated signaling and play a critical role in the induction of Type I interferons (IFN) and several chemokines in infected cells. We and others have shown that in cells infected both with RNA and DNA viruses these factors that reside in the cytoplasm are phosphorylated and translocated to nucleus where they form part of the transcription complex assembled on the promoters of IFNA and IFNB genes. There is also growing evidence that different viruses target the activation and function of cellular IRF-3 and IRF-7 to overcome the innate immune response. Studies of the immune control of HIV-1 infection has focused on the role of adaptive cellular antiviral response, while much less is known about the role of innate immune mechanisms in the control of HIV-1 infection. To fill this gap, the aim of the proposed study is to analyze the role of lRFs in the HIV mediated innate responses. The study has three aims: Aim1. The role of IRF-3, IRF-5 and IRF-7 in HIV replication. Here we shall determine how the expression levels of IRFs and their constitutively active mutants modulate HIV-1 replication and infection. Aim 2. Postranslational activation of IRF by HlV-1 mediated signaling. In this study we shall examine whether HIV-1 stimulated signaling cascades induce phosphorylation of IRFs, their nuc]ear translocation and transcription activation. Aim 3. The role of Nef in expression/activation of IRF factors. We shall determine whether Nef stimulates expression of iRF-3, 5 or 7 and induces their phosphoryJation and nuclear translocation or whether it blocks the function of these IRFs. This study should provide some basic insight into the role of innate response in control of HIV-1 infection. A better understanding of the initial antiviral immunity is essential for understanding HIV-1 pathogenesis and may be instrumental for developing new antiviral therapies.